{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:04:32Z","timestamp":1791421472457,"version":"4.3.3"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T00:00:00Z","timestamp":1553212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/M027341\/1"],"award-info":[{"award-number":["EP\/M027341\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The treatment of enteric bacterial infections using oral bacteriophage therapy can be challenging since the harsh acidic stomach environment renders phages inactive during transit through the gastrointestinal tract. Solid oral dosage forms allowing site-specific gastrointestinal delivery of high doses of phages, e.g., using a pH or enzymatic trigger, would be a game changer for the nascent industry trying to demonstrate the efficacy of phages, including engineered phages for gut microbiome modulation in expensive clinical trials. Spray-drying is a scalable, low-cost process for producing pharmaceutical agents in dry powder form. Encapsulation of a model Salmonella-specific phage (Myoviridae phage Felix O1) was carried out using the process of spray-drying, employing a commercially available Eudragit S100\u00ae pH-responsive anionic copolymer composed of methyl methacrylate-co-methacrylic acid formulated with trehalose. Formulation and processing conditions were optimised to improve the survival of phages during spray-drying, and their subsequent protection upon exposure to simulated gastric acidity was demonstrated. Addition of trehalose to the formulation was shown to protect phages from elevated temperatures and desiccation encountered during spray-drying. Direct compression of spray-dried encapsulated phages into tablets was shown to significantly improve phage protection upon exposure to simulated gastric fluid. The results reported here demonstrate the significant potential of spray-dried pH-responsive formulations for oral delivery of bacteriophages targeting gastrointestinal applications.<\/jats:p>","DOI":"10.3390\/ph12010043","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T06:56:52Z","timestamp":1553497012000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Microencapsulation of Salmonella-Specific Bacteriophage Felix O1 Using Spray-Drying in a pH-Responsive Formulation and Direct Compression Tableting of Powders into a Solid Oral Dosage Form"],"prefix":"10.3390","volume":"12","author":[{"given":"Gurinder K.","family":"Vinner","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Rezaie-Yazdi","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1855-8390","authenticated-orcid":false,"given":"Miika","family":"Leppanen","sequence":"additional","affiliation":[{"name":"Department of Physics, Department of Biological and Environmental Science, Nanoscience Center, University of Jyv\u00e4skyl\u00e4, 40014 Jyv\u00e4skyl\u00e4, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.F.","family":"Stapley","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Leaper","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9153-5761","authenticated-orcid":false,"given":"Danish J.","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.drup.2011.02.003","article-title":"Critical shortage of new antibiotics in development against multidrug-resistant bacteria\u2014Time to react is now","volume":"14","author":"Aronsson","year":"2011","journal-title":"Drug Resist. Updat."},{"key":"ref_2","unstructured":"The European Parliament and the Council of The European Union (2003). Regulation (EC) No 1831\/2003 of the European Parliament and of the Council of 22 September 2003 on Additives for Use in Animal Nutrition, European Union."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.tig.2016.01.005","article-title":"Manipulating Bacterial Communities by in situ Microbiome Engineering","volume":"32","author":"Sheth","year":"2016","journal-title":"Trends Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6412a1","article-title":"Outbreaks of Acute Gastroenteritis Transmitted by Person-to-Person Contact, Environmental Contamination, and Unknown Modes of Transmission\u2014United States, 2009\u20132013","volume":"64","author":"Wikswo","year":"2015","journal-title":"MMWR Surveill. Summ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3201\/eid1701.P11101","article-title":"Foodborne Illness Acquired in the United States\u2014Major Pathogens","volume":"17","author":"Scallan","year":"2011","journal-title":"Emerg. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1086\/318457","article-title":"Nontyphoidal Salmonellosis","volume":"32","author":"Hohmann","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.4315\/0362-028X.JFP-10-327","article-title":"Prevalence, Antibiotic Resistance, and Molecular Characterization of Salmonella Serovars in Retail Meat Products","volume":"74","author":"Hyeon","year":"2011","journal-title":"J. Food Prot."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"562","DOI":"10.4315\/0362-028X-73.3.562","article-title":"Serotype, Genotype, and Antimicrobial Susceptibility Profiles of Salmonella from Chicken Farms in Shanghai","volume":"73","author":"Liu","year":"2010","journal-title":"J. Food Prot."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12872","DOI":"10.1073\/pnas.1717162115","article-title":"Emergence of dominant multidrug-resistant bacterial clades: Lessons from history and whole-genome sequencing","volume":"115","author":"Klemm","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1128\/AEM.00785-09","article-title":"Phage therapy to reduce preprocessing Salmonella infections in market-weight swine","volume":"76","author":"Wall","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cis.2017.05.014","article-title":"Formulation, stabilisation and encapsulation of bacteriophage for phage therapy","volume":"249","author":"Malik","year":"2017","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Vinner, G.K., Vladisavljevic, G.T., Clokie, M.R.J., and Malik, D.J. (2017). Microencapsulation of Clostridium difficile specific bacteriophages using microfluidic glass capillary devices for colon delivery using pH triggered release. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186239"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.resmic.2018.05.011","article-title":"High precision microfluidic microencapsulation of bacteriophages for enteric delivery","volume":"169","author":"Vinner","year":"2018","journal-title":"Res. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1093\/ps\/86.9.1904","article-title":"Ability of bacteriophages isolated from different sources to reduce Salmonella enterica serovar enteritidis in vitro and in vivo","volume":"86","author":"Higgins","year":"2007","journal-title":"Poult. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s12223-011-0039-8","article-title":"The influence of external factors on bacteriophages\u2014Review","volume":"56","year":"2011","journal-title":"Folia Microbiol. (Praha)"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1128\/AEM.00246-08","article-title":"Microencapsulation of Bacteriophage Felix O1 into Chitosan-Alginate Microspheres for Oral Delivery","volume":"74","author":"Ma","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.foodhyd.2010.11.017","article-title":"Enhanced alginate microspheres as means of oral delivery of bacteriophage for reducing Staphylococcus aureus intestinal carriage","volume":"26","author":"Ma","year":"2012","journal-title":"Food Hydrocoll."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/mabi.201200109","article-title":"Novel Biopolymer Matrices for Microencapsulation of Phages: Enhanced Protection Against Acidity and Protease Activity","volume":"12","author":"Dini","year":"2012","journal-title":"Macromol. Biosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.foodres.2012.12.037","article-title":"Whey protein improves survival and release characteristics of bacteriophage Felix O1 encapsulated in alginate microspheres","volume":"52","author":"Tang","year":"2013","journal-title":"Food Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Colom, J., Cano-Sarabia, M., Otero, J., Ar\u00ed\u00f1ez-Soriano, J., Cort\u00e9s, P., Maspoch, D., and Llagostera, M. (2017). Microencapsulation with alginate\/CaCO3: A strategy for improved phage therapy. Sci. Rep., 7.","DOI":"10.1038\/srep41441"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.lwt.2014.08.012","article-title":"Preparation and characterization of dry powder bacteriophage K for intestinal delivery through oral administration","volume":"60","author":"Tang","year":"2015","journal-title":"LWT Food Sci. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ijpharm.2015.04.053","article-title":"Pharmaceutical spray freeze drying","volume":"488","author":"Wanning","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.1002\/jps.22715","article-title":"Spray-Dried Respirable Powders Containing Bacteriophages for the Treatment of Pulmonary Infections","volume":"100","author":"Matinkhoo","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ijpharm.2014.06.026","article-title":"Instability of bacteriophages in spray-dried trehalose powders is caused by crystallization of the matrix","volume":"472","author":"Vandenheuvel","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Leung, S.S.Y., Parumasivam, T., Nguyen, A., Gengenbach, T., Carter, E.A., Carrigy, N.B., Wang, H., Vehring, R., Finlay, W.H., and Morales, S. (2017). Effects of storage conditions on the stability of spray dried, inhalable bacteriophage powders. Int. J. Pharm.","DOI":"10.1016\/j.ejpb.2018.02.033"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.4315\/0362-028X-73.7.1304","article-title":"Oral delivery systems for encapsulated bacteriophages targeted at Escherichia coli O157: H7 in feedlot cattle","volume":"73","author":"Stanford","year":"2010","journal-title":"J. Food Prot."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S1461-5347(99)00237-0","article-title":"An overview of the different excipients useful for the direct compression of tablets","volume":"3","author":"Jivraj","year":"2000","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1080\/03602550600685275","article-title":"Spray drying of biopharmaceuticals: Stability and process considerations","volume":"24","author":"Ameri","year":"2006","journal-title":"Dry Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.bbapap.2013.01.020","article-title":"Unraveling protein stabilization mechanisms: Vitrification and water replacement in a glass transition temperature controlled system","volume":"1834","author":"Grasmeijer","year":"2013","journal-title":"Biochim. Biophys. Acta Proteins Proteom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ijfoodmicro.2006.04.047","article-title":"Evaluation of the natural virucidal activity of teas for use in the phage amplification assay","volume":"111","author":"Dodd","year":"2006","journal-title":"Int. J. Food Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1006\/cryo.2000.2244","article-title":"Literature review: Supplemented phase diagram of the trehalose-water binary mixture","volume":"40","author":"Chen","year":"2000","journal-title":"Cryobiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.ejpb.2012.12.022","article-title":"Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections","volume":"84","author":"Vandenheuvel","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/12\/1\/43\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:39:52Z","timestamp":1760186392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/12\/1\/43"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,22]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["ph12010043"],"URL":"https:\/\/doi.org\/10.3390\/ph12010043","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,22]]}}}